Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk.To develop effective therapies, we should establish the causal link between serum calcium levels and AD.Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate.IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude.In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.